Presence of defective NK cells in HIV-1 individuals indicates that HIV-1 infection compromises the nnate as well as the adaptive immune response. Though HIV-1 viral proteins are known to contribute to NK cell dysfunction and innate immunity, the mechanism(s) by which these viral proteins impair NK cell function is not well understood. We are particularly interested in the potential of HIV-1 Vpr, in immunopathogenesis and disease progression based on: our preliminary studies indicating the ability of Vpr to dysregulate antigen presenting cells and T cells directly at the cellular and molecular level, the ability of Vpr to compromise adaptive immune response through APC-T cell cross talk, and impair the function of NK cell function and effector molecules. Furthermore, the significance of Vpr in pathogenesis is further bolstered by the recent study indicating the presence of free Vpr in infected targets and uninfected bystander cells in vivo. Together these studies support our hypothesis that HIV-1 Vpr alters NK cell function and innate immunity either by directly impairing NK cells or through infected DC subsets mediated NK-DC cross talk. Thus, the major goal of this project is: (i) to determine how Vpr affects the NK cell function and phenotypes directly in the context of infection and exposure; (ii) to define the mechanisms and consequence of NK cell function indirectly through Vpr impaired DC subsets via DC-NK cell cross talk; and (iii) to delineate the effect of Vpr on NK cell receptors and signaling pathways that regulates NK cell function and innate immunity.